The present invention relates to an improved process for the preparation of organomagnesium compounds from organohalides and magnesium metal in the presence of transition metal catalysts and an activity-enhancing main group metal component.
Grignard compounds are usually prepared by reacting organic halides with magnesium in an ethereal solvent; in certain cases, they can also be prepared in hydrocarbons (Comprehensive Organometallic Chemistry II, Vol. 1, 1995, p. 58-63; Comprehensive Organometallic Chemistry I, Vol. 1, 1982, p. 155; Chem. Ber. 1990, 123, 1507 and 1517; Houben-Weyl, Methoden der organischen Chemie, 1973, 13/2a, 53-192).
However, there is a wide variety of organic halogen compounds, including, in particular, aromatic, vinylic and heterocyclic chloro compounds, with which the Grignard reaction proceeds hesitantly, with low yields, poorly or not at all. For increasing the reactivity of magnesium towards such halides, numerous methods are known which are based on physical (grinding, ultrasonication, metal vaporization) or chemical (entrainment method, Rieke method, dehydrogenation of magnesium hydride, reversible formation of magnesium anthracene) activation of magnesium (Active Metalsxe2x80x94Preparation, Characterization, Applications, A. Fxc3xcrstner (Ed.), Verlag Chemie, 1996). Further, a process for the preparation of Grignard compounds is known which is based on the physical and chemical activation of the magnesium metal employed (DE 27 55 300 A1, Schering A G). Thus, prior to performing the Grignard reaction, the magnesium metal is ground in the presence of organometallic aluminum, boron or zinc compounds in which the organo groups may also be partly substituted by halogens, hydrogen or alkoxy groups, and after the addition of organomagnesium compounds, it is converted to the corresponding Grignard compounds without further grinding with organyl halides. As catalysts for the Grignard reaction, anthracene or magnesium anthracene and their derivatives are known; however, they can be employed only in the case of allyl, propargyl and benzyl halides (Chem. Ber. 1990, 123, 1507). There are drawbacks in the mentioned methods in that they are either relatively tedious and expensive or subjected to limitations in application or effectiveness, or result in an increased consumption of magnesium (entrainment method: J. Org. Chem. 1959, 24, 504). Therefore, there is still a need for effective and economical methods for the preparation of Grignard compounds from the above mentioned inert organic halogen compounds which are not subject to the mentioned draw-backs, and with the proviso that conventional, commercially available magnesium grades can be used.
According to the Patent Application PCT/WO 98/02443 filed by the Studiengesellschaft Kohle, which corresponds to U.S. Ser. No. 09/214,369, filed Jan. 5, 1999, a process for the preparation of Grignard compounds is known which is characterized in that organic halides are reacted with magnesium metal in an ethereal solvent in the presence of catalysts consisting of inorganic Grignard reagents of transition metals having the general formula [M(MgX)m(MgX2)n]2, wherein M is a transition metal of Periodic Table groups 4-10, X is a halogen, m=1, 2, 3, n=0xe2x88x921, and optionally anthracene or substituted anthracenes or their Mg adducts and/or magnesium halides as cocatalysts. Iron halides and manganese halides are considered the preferred catalyst components according to the mentioned process. A preferred mode of carrying out the process involves performing the reaction of organic chlorine compounds with magnesium powder in the presence of catalysts prepared from iron or manganese halides, 9,10-diphenylanthracene, magnesium halide and excess Mg powder in THF, monoglyme or diglyme.
According to the Patent Application PCT/EP 98/08056 filed by the Studiengesell-schaft Kohle mbH, which corresponds to U.S. Ser. No. 09/581,874, filed Jun. 19, 2000, transition metal compounds in which elements of groups 15 or 16 (preferably N or O) are bonded to the transition metal are also suitable catalysts. Particularly preferred are those transition metal catalysts which contain Fe, Mn, Co and Cu bound to alkoxy, aryloxy, amido and phthalocyanine groups.
Surprisingly, it has now been found that the catalytic activity of the transition metal catalysts in which one or more elements selected from groups 14, 15, 16 or 17 are bonded to a metal selected from the metals of groups 3, 4, 5, 6, 7, 8, 9, 10 or 11 can be significantly improved by the addition of a main group metal component (Angew. Chem. 2000, 112, No. 24, 4788-4790). For this purpose, compounds of main group metals of Periodic Table groups 1, 2 and 13 (especially Li, Na, Mg, Al or B) are used in which one or more elements of Periodic Table groups 14, 15, 16 or 17 (especially C, N, O or halogens) or hydrogen are bonded to the metal. The main group metal additional components according to the invention are preferably employed in the form of alkyl, aryl, alkoxy, aryloxy, alkylamido, arylamido, phthalocyanine, halogen and/or hydrogen compounds. Some of these additional components may also be formed in situ (such as RMgX, formed from RX, where R is an alkyl or aryl residue and X is a halogen atom, and Mg metal, being present in excess). The said alkyl, alkoxy or alkylamido compounds are preferably employed with a chain length of from C1 to C16, whereas the aryl, aryloxy or arylamido compounds are preferably employed as phenyl compounds or substituted compounds of this kind, and the halogens are preferably employed in the form of chlorine, bromine or iodine.
The transition metal catalyst comprises a transition metal selected from Periodic Table groups 3, 4, 5, 6, 7, 8, 9, 10 or 11, and one or more elements selected from groups 14, 15, 16 or 17 bonded to the transition metal. The transition metal catalyst, for example, contains Fe, Mn, Co or Cu.
The additional main group metal component used according to the present process includes, for example, Grignard compounds (such as EtMgCl, phenyl-MgCl), diorganomagnesium compounds (such as diethylmagnesium), magnesium hydride, HMgCl, organomagnesium alcoholates (such as phenyl-MgOEt), magnesium phthalocyanine, lithium hydride, Li, Na, Al or B organyls (such as triethylaluminum, butyllithium, triphenylboron) as well as diorganoaluminum hydride and chloride (such as diisobutylaluminum hydride or diethylaluminum chloride).
The main group metal additional components of the present process (e.g. AlEt3 and EtMgBr) alone do not cause catalysis of the Grignard reaction (Example 9, Comparative Examples); however, when used together with the transition metal compounds mentioned, enhanced catalytic effects are observed.
The catalyst components according to the invention reduce the transition metal compound into a form which is particularly active catalytically. Thus, they do not function as mere magnesium metal activation agents (such as the organoaluminum, organoboron or organozinc compounds in DE 27 55 300 A1, Schering A G), but they are chemical reactants in the preparation of particularly active transition metal catalysts (see Examples 1, 2, 9, and Comparative Examples), where they are consumed partially or completely. Thus, for example, ferrous chloride will react with the organomagnesium compound n-heptylmagnesium bromide with reduction of the iron and release of heptane and heptene to yield a particularly active catalyst.
Also, it was found that, in addition to the catalysts of transition metals described in PCT/WO 98/02443 and PCT/EP 98/08056, organometallic compounds of these elements, such as metallocenes, e.g. ferrocene, and substituted metallocenes can also be used as catalysts for Grignard synthesis.
The magnesium metal is employed in the form of commercially available powders, dusts, raspings, granules, chips or turnings (preferably as a powder). If necessary, the magnesium metal may be employed in an activated form or be continuously activated superficially, while the reaction is performed, using agitating, grinding or cutting devices (Example 3).
In addition, halides of Periodic Table 1st and 2nd main group metals (preferably Li and Mg) as well as ammonium halides and organoammonium halides, such as MgCl2, LiCl or NBu4Br, can be employed as cocatalysts. Magnesium halides, when used as cocatalysts, can also be generated in situ by the addition of, for example, 1,2-dihaloethane to the magnesium, which is present in excess (Example 5).
Anthracene and substituted anthracene compounds, especially 9,10-disubstituted anthracenes (preferably 9,10-diphenylanthracene), or their magnesium adducts can be used as further cocatalysts (Example 17). Anthracene has the specific property of dissolving magnesium metal. Magnesium anthracene, which is produced thereby, can readily release its magnesium atom in Grignard reactions to regenerate anthracene, which can then again dissolve magnesium metal. Thus, anthracene and some substituted anthracenes, especially 9,10-diphenylanthracene, in catalytic amounts can provide xe2x80x9cquasi-soluble magnesiumxe2x80x9d and thus function as phase-transfer catalysts (Accounts of Chem. Res., 21, 261-267 (1988); Chem. Ber. 123 (1990), 1529-1535).
The process is preferably performed in ethereal solvents (especially THF, diglyme and monoglyme), preferably at room temperature and up to the boiling temperature of the solvent; due to the high activity, the reactions may also be performed at lower temperatures.
A preferred, simplified mode of performing the present process involves the use of the main group metal compound, required to enhance the activity of the transition metal compound (e.g. ferrous halide), in the form of a Grignard compound. The latter may also be formed in situ from an organohalogen compound and the Mg metal, which is present in excess. The organohalogen compounds are preferably used as alkyl or aryl halides; alkyl compounds having a chain length of from C1 to C16 and aryl groups in the form of phenyl groups or substituted compounds of this kind being preferred. In particular, the halogens are employed in the form of chlorine, bromine or iodine. The molar ratio of the organohalogen compound to the transition metal catalyst is  greater than 0.2:1, preferably between 1 and 5:1.
The inventive process leads to significantly higher catalyst activity as compared to the known processes. The use of the additional main group metal compound which reduces the transition metal component into a particularly active form enables even particularly difficult Grignard syntheses to be realized in high yields.
In particular, the synthesis of hardly accessible Grignard compounds from aromatic chlorine compounds, such as chlorobenzene and chlorine-containing condensed aromatics, such as chloronaphthalene, chloroanthracene and chlorophenanthrene, or substituted compounds of this kind having substituents consisting of alkyl, aryl, alkoxy, aryloxy, alkylamido and/or arylamido groups, and chlorine-containing heterocycles, especially aromatic chloroheterocycles with N, O or S heteroatoms, such as chloropyridine, chloroquinoline, chloropyrrole and chlorofurane or substituted compounds of this kind having substituents consisting of alkyl, aryl, alkoxy, aryloxy, alkylamido and/or arylamido groups, can be significantly improved according to the process of this invention.
The performance of the catalysis according to the invention is illustrated by examples involving particularly difficult reactions, namely the conversions of acetal-protected chlorobenzaldehyde (Examples 1-14), 5-chlorobenzodioxole (Examples 1s and 17) and 2-chloro-6-methoxypyridine (Example 16) to the corresponding Grignard compounds.
Using a Grignard reaction which could be performed only with low yields to date, namely the preparation of the Grignard compound of 4-chlorobenzaldehyde diethyl acetal, the dependence of the product yield on the quantity of main group metal used is clearly demonstrated for EtMgBr (preparation from EtBr in situ) as an example (Examples 1 and 2). In the mentioned processes of the Studiengesellschaft Kohle mbH, a maximum of 4 drops of ethyl bromide is employed for etching the Mg surface (Pearson, Cowan, Becker, J. Org. Chem. 24, 504, 1959). However, if 4 mol of EtBr is used per mole of ferrous chloride, the yield of isolated Grignard compound is 85% of theory (Example 2), whereas a Grignard yield of only 45% of theory is achieved when 0.2 mol of EtBr is used per mole of ferrous chloride (by analogy with PCT/WO 98/02443 and PCT/EP 98/08056) under the same conditions (Example 2, Comparative Example).
For the catalytic preparation of the Grignard compounds of 5-chloro-1,3-benzodioxole (Example 15) and 2-chloro-6-methoxypyridine (Example 16), it was also established that significantly higher Grignard yields can be achieved when a significantly higher amount of ethyl bromide is employed as compared with the known processes.
An explanation of these facts was provided, inter alia, by examining the centrifuged catalyst solutions for their iron contents. If ferrous chloride in THF at room temperature is added to excess Mg powder and ethylmagnesium bromide (formed in situ from EtBr and Mg), the amount of dissolved Fe increases from 40 to 85% as the EtMgBr content increases.
The use of the mentioned main group organometallic compounds in the formation of the catalyst in equimolar or higher amounts (as compared to substoichiometric amounts in the Patent Application filed by the Studiengesellschaft Kohle, PCT/WO 98/02443) causes the iron halide to dissolve quickly, for the most part thereof, rather than precipitating in metallic form, which contributes to the formation of a particularly active catalyst system. Ethyl bromide, which was used only in minor amounts in the Patent Application PCT/WO 98/02443 (0.2 mol of EtBr per mole of iron halide) and only served to etch the surface of the Mg particles, is an activity-enhancing component of the present catalyst system when used in equimolar amounts or in excess.
In addition to EtMgBr (prepared in situ), for the first time, Li, Na, Mg, Al and B compounds with hydride, halogen, ethyl, butyl, heptyl, phenyl, alkoxy, aryloxy and phthalocyanine groups, inter alia, which can be combined with various transition metal compounds, were also employed for this purpose, e.g.: phenylmagnesium bromide+Co-phthalocyanine (Example 11), butyllithium+FeCl2 (Example 8), AlEt3+FeCl2 (Example 9), or Mg-phthalocyanine+FeCl2 (Example 6). The wide variety of possible catalyst combinations and cocatalysts in the present process offers the possibility of a problem-oriented catalyst design.
The invention is illustrated by way of the following Examples without being limited thereto. The experiments were performed under a protective gas (argon). Anhydrous solvents deprived of air were employed. In all experiments, commercially available Mg powder (270 mesh; i.e. particle size of about 53 xcexcm) was used. For this purpose, anhydrous MgCl2 was prepared from 1,2-dichloroethane and magnesium powder in THF or formed in situ.